Melatonin: functions and mechanisms of action in placental trophoblast

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Over the past 14 years, our research program funded by NSERC-discovery grant has allowed demonstrating a crucial role of melatonin in placental function. Our and others research have shown that melatonin has unsuspected beneficial actions on the peripheral reproductive organs, one of which very likely relates to its ability to obviate oxidative stress and placental dysfunction. This research proposal, which is a direct extension of our ongoing NSERC-supported program, aim to understand the role of melatonin and its receptors at the maternal-fetal interface, the placenta, and to develop a cellular model to study the regulation and protective function of this indolamine. The short-term goals of the next 5 years are to elucidate the mechanisms by which melatonin directly and via the activation of its receptors protects the normal placental cells against hypoxia/reoxygenation-induced damage and has cytotoxic effects on placental tumor cells. Specifically, in primary placental villous trophoblast cells, we will dissect the mechanism underlying melatonin protective action on hypoxia/reoxygenation-induced apoptosis and oxidative stress; and determine how melatonin regulates autophagy, endoplasmic reticulum-stress and mitochondrial function. We hypothesize that the differential effects of melatonin in normal trophoblast cells (cytoprotective) and in tumor trophoblast cells (cytotoxic) is mediated, in part, throughout the activation of MT1 and MT2 receptors. Specific Objectives: Specifically, in trophoblast cells, we will dissect the mechanism by which melatonin and its receptors regulate (1) mitochondrial (intrinsic) apoptosis and oxidative stress; (2) autophagy and mitophagy; and (3) endoplasmic reticulum (ER)-stress and mitochondrial function. These research objectives will be addressed using primary cultures of villous trophoblasts from term human placenta, and BeWo human placental choriocarcinoma cell line cultured under normoxia (8% O2) or subject to hypoxia/reoxygenation (4 h hypoxia (0.5% O2) following by 18 h reoxygenation (8% O2)) to induce homoeostasis disruption. Relevance: Our program of research, using trophoblast cells, uses novel approaches to discover the mechanisms by which melatonin plays a cytoprotective (pro-survival) or cytotoxic (pro-death) role. Collectively, the proposed research program will advance our fundamental knowledge of the role of melatonin and its receptors in placenta as well as in normal and abnormal cellular processes (e.g. sleep, cancer, neurodevelopment and reproductive function) and open the way for the development of new preventive and therapeutic molecules in these areas. Melatonin has been suggested for the potential prevention and treatment of a variety of disorders, including obstetric complications, depression, cancer, and neurodegenerative disease.